A new MPZ mutation associated with a mild CMT1 phenotype presenting with recurrent nerve compression

P0 is a transmembrane protein of the immunoglobulin superfamily that plays a role in myelin structure and function. Myelin protein zero gene (MPZ) mutations usually cause a demyelinating variant of Charcot-Marie-Tooth disease type 1B (CMT1B), but there is a wide spectrum of phenotypic manifestation of these mutations. We describe three patients from one family and one separate patient who presented with a demyelinating neuropathy. Some had recurrent lesions at compression sites mimicking hereditary neuropathy with liability to pressure palsies (HNPP). A heterozygous nonsense mutation (Tyr145Stop) corresponding to a T-to-A transition at nucleotide position 435 in exon 3 of the MPZ gene was identified in all patients. This mutation leads to an extracellular truncated protein, which may explain the mild phenotype. Therefore, such MPZ gene mutations should be searched for in cases of demyelinating neuropathy with acute nerve compression as well as in cases of the HNPP phenotype associated with normal the PMP22 gene.     

Report of a novel mutation in the PMP22 gene causing an axonal neuropathy

Introduction: Point mutations in the peripheral myelin protein 22 (PMP22) gene rarely cause the hereditary neuropathies Charcot–Marie–Tooth disease type 1A (CMT1A) and hereditary neuropathy with liability to pressure palsies (HNPP), both of which show a demyelinating phenotype. Methods: In this study we characterized a family with an axonal neuropathy. Results: Three family members carried a heterozygous point mutation of the PMP22 gene, resulting in amino acid substitution R159C. Screening of 185 healthy controls did not reveal the R159C allele in any case. Discussion: The novel R159C mutation represents a very rare case of a dominant PMP22 mutation causing an axonal neuropathy. Muscle Nerve, 2011     

Peripheral Myelin Protein 22 gene duplication with atypical presentations: A new example of the wide spectrum of Charcot-Marie-Tooth 1A disease

Charcot-Marie-Tooth type 1A (CMT1A) and hereditary neuropathy with liability to pressure palsies (HNPP) are both autosomal-dominant disorders linked to peripheral myelin anomalies. CMT1A is associated with a Peripheral Myelin Protein 22 (PMP22) duplication, whereas HNPP is due to a PMP22 deletion on chromosome 17. In spite of this crucial difference, we report three observations of patients with the 1.4 megabase CMT1A duplication and atypical presentation (electrophysiological, clinical or pathological): a 10 year-old girl with tomaculous lesions on nerve biopsy; a 26 year-old woman with recurrent paresthesiae and block conduction on the electrophysiological study; a 46 year-old woman with transient recurrent nerve palsies mimicking HNPP. These observations highlight the wide spectrum of CMT1A and the overlap between CMT1A and HNPP (both linked to the PMP22 gene), and finally illustrate the complexity of the genotype–phenotype correlations in Charcot-Marie-Tooth diseases.     

A novel 3'-splice site mutation in peripheral myelin protein 22 causing hereditary neuropathy with liability to pressure palsies

Hereditary neuropathy with liability to pressure palsies (HNPP) is an autosomal dominant, demyelinating peripheral neuropathy. Clinical hallmarks are recurrent painless focal neuropathies mostly preceded by minor trauma or compression at entrapment sites of peripheral nerves. In the majority of the patients, HNPP is caused by a 1.5 Mb deletion on chromosome 17p11.2-p12 containing the peripheral myelin protein 22 (PMP22) gene. Point mutations within this gene are reported in only a few families. We report a novel mutation in the PMP22 gene in a Spanish family with HNPP. The mutation is a 3' splice-site mutation, preceding coding exon 3 (c.179-1 G>C), causing a mild HNPP phenotype.     

Inherited focal, episodic neuropathies

Hereditary neuropathy with liability to pressure palsies (HNPP; also called tomaculous neuropathy) is an autosomal-dominant disorder that produces a painless episodic, recurrent, focal demyelinating neuropathy. HNPP generally develops during adolescence, and may cause attacks of numbness, muscular weakness, and atrophy. Peroneal palsies, carpal tunnel syndrome, and other entrapment neuropathies may be frequent manifestations of HNPP. Motor and sensory nerve conduction velocities may be reduced in clinically affected patients, as well as in asymptomatic gene carriers. The histopathological changes observed in peripheral nerves of HNPP patients include segmental demyelination and tomaculous or “sausage-like” formations. Mild overlap of clinical features with Charcot-Marie-Tooth (CMT) disease type 1 (CMT1) may lead patients with HNPP to be misdiagnosed as having CMT1. HNPP and CMT1 are both demyelinating neuropathies, however, their clinical, pathological, and electrophysiological features are quite distinct. HNPP is most frequently associated with a 1.4-Mb pair deletion on chromosome 17p12. A duplication of the identical region leads to CMT1A. Both HNPP and CMT1A result from a dosage effect of the PMP22 gene, which is contained within the deleted/duplicated region. This is reflected in reduced mRNA and protein levels in sural nerve biopsy samples from HNPP patients. Treatment for HNPP consists of preventative and symptom-easing measures. Hereditary neuralgic amyotrophy (HNA; also called familial brachial plexus neuropathy) is an autosomal-dominant disorder causing episodes of paralysis and muscle weakness initiated by severe pain. Individuals with HNA may suffer repeated episodes of intense pain, paralysis, and sensory disturbances in an affected limb. The onset of HNA is at birth or later in childhood with prognosis for recovery usually favorable; however, persons with HNA may have permanent residual neurological dysfunction following attack(s). Episodes are often triggered by infections, immunizations, the puerperium, and stress. Electrophysiological studies show normal or mildly prolonged motor nerve conduction velocities distal to the affected brachial plexus. Pathological studies have found axonal degeneration in nerves examined distal to the plexus abnormality. In some HNA pedigrees there are characteristic facial features, including hypotelorism. The prognosis for recovery of normal function of affected limbs in HNA is good, although recurrent episodes may cause residual deficits. HNA is genetically linked to chromosome 17q25, where mutations in the septin-9 (SEPT9) gene have been found.     

A family with a novel frameshift mutation in the PMP22 gene (c.433_434insC) causing a phenotype of hereditary neuropathy with liability to pressure palsies

Hereditary neuropathy with liability to pressure palsies is usually due to PMP22 deletion. Point mutations of PMP22 causing an hereditary neuropathy with liability to pressure palsies phenotype are rare. We describe a clinical and electrodiagnostic phenotype of hereditary neuropathy with liability to pressure palsies in a 21-year-old woman, which led to our detecting a novel frameshift mutation of PMP22. This mutation was also found in her mother and brother and corresponded to an insertion of one cytidine between nucleotides 433 and 434 in the last coding exon (c.433_434insC). The mutated PMP22 protein lacks the last 15 amino acids and has a modified C terminus lengthened to 221 residues instead of 160 (Leu145fsX222). The mother and the proband had a clinical and electrophysiological hereditary neuropathy with liability to pressure palsies phenotype. The brother was asymptomatic, but the results of electrodiagnostic tests were suggestive of hereditary neuropathy with liability to pressure palsies. This observation of a new mutation mostly leading to a PMP22 haploinsufficiency provides further evidence of the diversity of phenotypes associated with frameshift PMP22 mutations.     

Inherited focal, episodic neuropathies: hereditary neuropathy with liability to pressure palsies and hereditary neuralgic amyotrophy

Hereditary neuropathy with liability to pressure palsies (HNPP; also called tomaculous neuropathy) is an autosomal-dominant disorder that produces a painless episodic, recurrent, focal demyelinating neuropathy. HNPP generally develops during adolescence, and may cause attacks of numbness, muscular weakness, and atrophy. Peroneal palsies, carpal tunnel syndrome, and other entrapment neuropathies may be frequent manifestations of HNPP. Motor and sensory nerve conduction velocities may be reduced in clinically affected patients, as well as in asymptomatic gene carriers. The histopathological changes observed in peripheral nerves of HNPP patients include segmental demyelination and tomaculous or "sausage-like" formations. Mild overlap of clinical features with Charcot-Marie-Tooth (CMT) disease type 1 (CMT1) may lead patients with HNPP to be misdiagnosed as having CMT1. HNPP and CMT1 are both demyelinating neuropathies, however, their clinical, pathological, and electrophysiological features are quite distinct. HNPP is most frequently associated with a 1.4-Mb pair deletion on chromosome 17p12. A duplication of the identical region leads to CMT1A. Both HNPP and CMT1A result from a dosage effect of the PMP22 gene, which is contained within the deleted/duplicated region. This is reflected in reduced mRNA and protein levels in sural nerve biopsy samples from HNPP patients. Treatment for HNPP consists of preventative and symptom-easing measures. Hereditary neuralgic amyotrophy (HNA; also called familial brachial plexus neuropathy) is an autosomal-dominant disorder causing episodes of paralysis and muscle weakness initiated by severe pain. Individuals with HNA may suffer repeated episodes of intense pain, paralysis, and sensory disturbances in an affected limb. The onset of HNA is at birth or later in childhood with prognosis for recovery usually favorable; however, persons with HNA may have permanent residual neurological dysfunction following attack(s). Episodes are often triggered by infections, immunizations, the puerperium, and stress. Electrophysiological studies show normal or mildly prolonged motor nerve conduction velocities distal to the affected brachial plexus. Pathological studies have found axonal degeneration in nerves examined distal to the plexus abnormality. In some HNA pedigrees there are characteristic facial features, including hypotelorism. The prognosis for recovery of normal function of affected limbs in HNA is good, although recurrent episodes may cause residual deficits. HNA is genetically linked to chromosome 17q25, where mutations in the septin-9 (SEPT9) gene have been found.     

Molecular alterations resulting from frameshift mutations in peripheral myelin protein 22: implications for neuropathy severity

Alterations in peripheral myelin protein 22 (PMP22) expression are associated with a heterogeneous group of hereditary demyelinating peripheral neuropathies. Two mutations at glycine 94, a single guanine insertion or deletion in PMP22, result in different reading frameshifts and, consequently, an extended G94fsX222 or a truncated G94fsX110 protein, respectively. Both of these autosomal dominant mutations alter the second half of PMP22 and yet are linked to clinical phenotypes with distinct severities. The G94fsX222 is associated with hereditary neuropathy with liability to pressure palsies, whereas G94fsX110 causes severe neuropathy diagnosed as Dejerine-Sottas disease or Charcot-Marie-Tooth disease type IA. To investigate the subcellular changes associated with the G94 frameshift mutations, we expressed epitope-tagged forms in primary rat Schwann cells. Biochemical and immunolabeling studies indicate that, unlike the wild-type protein, which is targeted for the plasma membrane, frameshift PMP22s are retained in the cell, prior to reaching the medial Golgi compartment. Similar to Wt-PMP22, both frameshift mutants are targeted for proteasomal degradation and accumulate in detergent-insoluble, ubiquitin-containing aggregates upon inhibition of this pathway. The extended frameshift PMP22 shows the ability to form spontaneous aggregates in the absence of proteasome inhibition. On the other hand, Schwann cells expressing the truncated protein proliferate at a significantly higher rate than Schwann cells expressing the wild-type or the extended PMP22. In summary, these results suggest that a greater potential for PMP22 aggregation is associated with a less severe phenotype, whereas dysregulation of Schwann cell proliferation is linked to severe neuropathy.     

Inherited peripheral neuropathy

Hereditary disorders of the peripheral nerves constitute a group of frequently encountered neurological diseases. Charcot-Marie-Tooth neuropathy type 1 (CMT1) is genetically heterogeneous and characterized by demyelination with moderately to severely reduced nerve conduction velocities, absent muscle stretch reflexes and onion bulb formation. Genetic loci for CMT1 map to chromosome 17 (CMT1A), chromosome 1 (CMT1B), and another unknown autosome (CMT1C). CMT1A is most often associated with a tandem 1.5-megabase (Mb) duplication in chromosome 17p11.2-12, or in rare patients may result from a point mutation in the peripheral myelin protein-22 (PMP22) gene. CMT1 B result from point mutations in the myelin protein zero (Po or MPZ) gene. The molecular defect in CMT1 C is unknown. Mutations in the early growth response 2 gene (EGR2) are also associated with demyelinating neuropathy. Other rare forms of demyelinating peripheral neuropathies map to chromosome 8q, 10q, and 11q. X-linked Charcot-Marie-Tooth neuropathy (CMTX), which has clinical features similar to CMT1, is associated with mutations in the connexin32 gene. Charcot-Marie-Tooth neuropathy type 2 (CMT2) is characterized by normal or mildly reduced nerve conduction velocity with decreased amplitude and axonal loss without hypertrophic features. One form of CMT2 maps to chromosome 1 p36 (CMT2A), another to chromosome 3p (CMT2B) and another to 7p (CMT2D). Dejerine-Sottas disease (DSD), also called hereditary motor and sensory neuropathy type III (HMSNIII), is a severe, infantile-onset demyelinating polyneuropathy that may be associated with point mutations in either the PMP22 gene or the Po gene and shares considerable clinical and pathological features with CMT1. Hereditary neuropathy with liability to pressure palsies (HNPP) is an autosomal dominant disorder that results in a recurrent, episodic demyelinating neuropathy. HNPP is associated with a 1.5-Mb deletion in chromosome 17p11.2-12 and results from reduced expression of the PMP22 gene. CMT1A and HNPP are reciprocal duplication/deletion syndromes originating from unequal crossover during germ cell meiosis.     

Variable phenotypes are associated with PMP22 missense mutations

Charcot-Marie-Tooth disease (CMT) is the commonest hereditary neuropathy encompassing a large group of clinically and genetically heterogeneous disorders. The commonest form of CMT, CMT1A, is usually caused by a 1.4 megabase duplication of chromosome 17 containing the PMP22 gene. Mutations of PMP22 are a less common cause of CMT. We describe clinical, electrophysiological and molecular findings of 10 patients carrying PMP22 missense mutations. The phenotype varied from mild hereditary neuropathy with liability to pressure palsies (HNPP) to severe CMT1. We identified six different point mutations, including two novel mutations. Three families were also found to harbour a Thr118Met mutation. Although PMP22 point mutations are not common, our findings highlight the importance of sequencing the PMP22 gene in patients with variable CMT phenotypes and also confirm that the PMP22 Thr118Met mutation is associated with a neuropathy albeit with reduced penetrance.     

Four novel point mutations in the PMP22 gene with phenotypes of HNPP and Dejerine-Sottas neuropathy

We report four novel point mutations in the PMP22 gene with two different phenotypes: mutation p.Ser79Thr arose de novo in a patient with the Dejerine-Sottas neuropathy (DSN) phenotype; and mutations c.78+5 G>A, c.320-1 G>C, and p.Trp140Stop segregated with HNPP in 5 families.Our findings show that point mutations in PMP22 may be more likely in HNPP patients than in CMT1 patients after exclusion of CMT1A/HNPP.     

Effects of PMP22 duplication and deletions on the axonal cytoskeleton

Axonal loss in Charcot-Marie-Tooth type 1A (CMT1A) is an important feature correlated with the functional disability in affected individuals. It is not known, however, how the most common genetic defect in Schwann cells (PMP22 duplication) causes the CMT1A phenotype and results in axonal loss. In this study, sural nerve segments from individuals with PMP22 duplications or deletions, causing the reciprocal disorder hereditary neuropathy with pressure palsies (HNPP), were grafted into the cut ends of the sciatic nerve of nude mice. The xenografts and host segments were studied at 2, 4, 6, 8, 12, and 16 weeks after grafting and compared with the controls from healthy volunteers. Within the CMT1A xenografts, the nude mice axons in the proximal part of the graft showed a significant increase in axonal area with an increase in the neurofilament and membranous organelle (mitochondria) density, compared with distal graft and distal host segments. A preferential distal axonal loss, associated with a perpetual axonal atrophy, degeneration, and axonal sprouting was observed over time, with increasing intensity at 8 to 16 weeks. These alterations were seen to a lesser extent in HNPP xenografts and were not observed in controls. In addition, the onset of regeneration-associated myelination was delayed, more significantly in HNPP xenografts than those of CMT1A. Our findings indicate that the PMP22 duplication in Schwann cells results in an impairment in the normal axonal cytoskeletal organization, resulting in distal axonal degeneration and fiber loss, and the affect of PMP22 deletion on axonal cytoskeleton is less deleterious. Ann Neurol 1999;45:16–24     

A Family Harboring CMT1A Duplication and HNPP Deletion

Charcot-Marie-Tooth disease type 1A (CMT1A) is associated with duplication of chromosome 17p11.2-p12, whereas hereditary neuropathy with liability to pressure palsies (HNPP), which is an autosomal dominant neuropathy showing characteristics of recurrent pressure palsies, is associated with 17p11.2-p12 deletion. An altered gene dosage of PMP22 is believed to the main cause underlying the CMT1A and HNPP phenotypes. Although CMT1A and HNPP are associated with the same locus, there has been no report of these two mutations within a single family. We report a rare family harboring CMT1A duplication and HNPP deletion.     

X-linked Charcot-Marie-Tooth disease: phenotypic expression of a novel mutation Ile127Ser in the GJB1 (connexin 32) gene

We report a family with X-linked dominant Charcot-Marie-Tooth disease (CMTX1). Three affected family members are described, who underwent detailed clinical, electrophysiological, molecular genetic, and histopathological studies. A novel isoleucine at position 127 with serine (Ile127Ser) mutation in the gap junction protein beta 1 (GJB1) gene was detected. The electrophysiological findings were consistent with a primary demyelinating neuropathy with secondary axonal loss and support this model of disease progression. All patients having the CMT phenotype and intermediate conduction velocities who are negative for CMT1A duplication/hereditary neuropathy with liability to pressure palsies (HNPP) deletion, and whose family shows a dominant trait without male-to-male transmission, should be screened for CMTX1.     

Molecular diagnosis of PMP22-associated neuropathies using fluorescence in situ hybridization (FISH) on archival peripheral nerve tissue preparations

Charcot-Marie-Tooth (CMT) syndrome type 1 and tomaculous neuropathy, also called hereditary neuropathy with liability to pressure palsies (HNPP), represent two groups of neurological disorders with different subtypes, which can be distinguished at the molecular level. It is known that a 1.5-mb region on chromosome 17p11.2– 12, which includes the gene for the peripheral myelin protein 22 kDa (PMP22), is duplicated in more than 95% of patients with CMT type 1A (CMT1A; gene dosage 3) and is deleted in about 90% of subjects suffering from HNPP (gene dosage 1). This duplication/deletion can be detected reliably by interphase-two-color fluorescence in situ hybridization (FISH). We report here a technique for extraction of nuclei from paraffin-embedded and cryofixed sural nerve biopsies for precise molecular diagnosis, employing interphase-two-color FISH in clinically diagnosed CMT1 or HNPP patients. Following this technique we were able to identify six CMT1A duplications in 13 clinically diagnosed CMT1 cases and five HNPP deletions in 6 clinically diagnosed HNPP cases; 8 control persons were included in this study. This is the first report on the use of FISH in the detection of 17p11.2–12 duplication and deletion in archival biopsy material. Received: 10 January 1997 / Revised, accepted: 3 March 1997     

Hereditary neuropathy with liability to pressure palsies: Association with central nervous system demyelination

Hereditary neuropathy with liability to pressure palsies (HNPP) is usually caused by a 1.5-Mb deletion in chromosome 17p11.2, the inverse mutation to the duplication seen in the majority of Charcot-Marie-Tooth type 1A (CMT 1A) patients. Although most patients with HNPP present with pressure palsies secondary to mild trauma, the clinical heterogeneity of the neuropathy has become more apparent following the discovery of the mutation. There are reports of central conduction abnormalities in CMT 1, however, there have been no previous reports of central nervous system (CNS) demyelination in HNPP. We report a case of HNPP with the typical DNA mutation whose clinical features and MRI of the brain suggested concurrent CNS demyelination. Further studies of possible CNS involvement in HNPP are warranted. © 1996 John Wiley & Sons, Inc.     

Screening for Charcot-Marie-Tooth type 1A and hereditary neuropathy with liability to pressure palsy in archival nerve biopsy samples by direct-double-differential PCR

Chromosomal imbalance of the peripheral myelin protein-22 gene (PMP22) is known to be the most frequent genetic abnormality in Charcot-Marie-Tooth disease type 1 (CMT1) and hereditary neuropathy with liability to pressure palsy (HNPP). We applied a new quantitative PCR method, the direct-double-differential PCR (dddPCR), to the gene dosage determination of PMP22. The method allows the quantification of the PMP22 gene copy number independently from DNA fragmentation, even in highly degraded DNA from up to 12-year-old sural nerve biopsy samples. Chromosomal imbalance of the PMP22 gene, which had been detected by examination of four microsatellites located directly adjacent to the PMP22 gene, between the CMT1A-repetition (CMT1A-REP) elements was reliably confirmed by the dddPCR. Using this method we unexpectedly identified two cases with PMP22 imbalance, although morphologically the neuropathies were of a neuronal or axonal type and not of a demyelinating type as usual. One sural nerve biopsy was from a 58-year-old male diabetes mellitus patient with a disproportionately severe polyneuropathy showing a heterozygous duplication of PMP22. The second biopsy exhibiting a heterozygous deletion of PMP22 was from a 58-year-old female patient with a more axonal than demyelinating type of neuropathy without typical tomaculous changes seemingly altered by exogenous, possibly traumatic factors other than diabetes mellitus. Thus, the dddPCR provides a fast and reliable diagnostic tool for the screening and identification of CMT1A and HNPP cases, which is fast and may be essential even when nerve biopsies show morphologically atypical changes. Received: 10 April 2000 / Accepted: 7 June 2000     

PMP22 Thr118Met is not a clinically relevant CMT1 marker

It is controversial if peripheral myelin protein 22 gene (PMP22) Thr 118Met represents a functionally irrelevant polymorphism or, since hemizygosity for this variant has been found in two patients with Charcot-Marie-Tooth disease type 1 (CMT1 patients), it can act as a recessive CMT1 mutation. To shed further light on this variant and its diagnostic value we searched for carriers in 1018 individuals from the German general population, in 104 probands with hereditary neuropathy with liability to pressure palsies (HNPP) who were carriers of the 1.5-Mb deletion frequently associated with this disorder, in 187 patients with the 1.5-Mb duplication, and in 22 patients with a CMT1 phenotype who did not have any detectable anomaly in the PMP22 gene. Using allele-specific PCR we identified 14 [allele frequency (AF)=0.007] in the German general population, one (AF=0.01) in the HNPP group and six (AF=0.016) and two (AF=0.05) carriers of the PMP22 Thr118Met mutation in the CMT1 groups with and without gene defect. Carriers from all groups showed nerve conduction velocities which did not differ from typical values for these groups. We conclude that the hemizygous occurrence of the 118Met allele does not usually cause CMT1. Because of previous reports on its association with disease, and because its allele product shows abnormalities in in vitro expression systems, it seems possible that this mutation, together with yet unidentified factors, predisposes to CMT1. Alternatively, previously reported disease associations occurred by chance, and the 118Met allele causes biochemical abnormalities irrelevant for CMT1 formation. In either case this mutation is not a clinically relevant disease marker. Received: 30 November 1999/Received in revised form: 31 March 2000/Accepted: 18 April 2000     

Dosage effects of PMP22 on nonmyelinating Schwann cells in hereditary neuropathy with liability to pressure palsies

Focal thickening of the myelin sheath, also known as tomacula, is a characteristic pathological feature of patients with hereditary neuropathy with liability to pressure palsies (HNPP). However, a deeper understanding of the pathology underlying unmyelinated fibers and nonmyelinating Schwann cells is required. Electron microscopic examination of sural nerve biopsy specimens was performed for 14 HNPP patients with peripheral myelin protein 22 (PMP22) deletion, and their results were compared to 12 normal controls and 14 Charcot–Marie–Tooth disease type 1A (CMT1A) patients with PMP22 duplication. The number of unmyelinated axons in a single axon-containing nonmyelinating Schwann cell subunit in the HNPP group significantly increased compared with that in normal controls (1.99 ± 0.66 vs. 1.57 ± 0.52, p < 0.05). Conversely, these numbers significantly decreased in the CMT1A group compared with those in normal controls (1.16 ± 0.16, p < 0.05). Some unmyelinated axons in patients with HNPP were incompletely surrounded by the cytoplasm of Schwann cells, almost as if the Schwann cells failed to form mesaxons; such failure in mesaxon formation was not observed in normal controls or in patients with CMT1A. These findings suggest that PMP22 dosage affects nonmyelinating as well as myelinating Schwann cells.